The present invention relates to nerve stimuli, and more particularly, to apparatus and methods for nerve-branch-specific action-potential activation, inhibition, and monitoring.
The nervous system is a network of billions of interconnected nerve cells, or neurons, that receive various types of stimuli and cause the body to respond appropriately. The neurons link the central nervous system (CNS) consisting of the brain and the spinal cord, with the body. A neuron usually has a cell body, dendrites that receive inputs, and an axon, an elongated nerve fiber that transmits electrical potentials as action potential. Efferent neurons send impulses peripherally to activate muscles or secretory cells, while afferent neurons convey sensory information centrally from the periphery.
The axon, the fiber-like, elongated portion of the nerve cell, conducts impulses in two directions, to and from the body of the nerve cell and transmits the information along the nervous system. Its function is somewhat analogous to a wire in an electric circuit. However, whereas in an electrical circuit, a wire allows the passage of a current, generally along its core, the axon, on the other hand, operates by the propagation of a potential difference along its plasma-membrane external surface, formed as a molecular lipid bilayer.
The propagating potential difference is referred to as action potential. It is an “all-or-nothing” phenomenon, described below:
1. Rest Condition: When at rest, sodium-potassium pumps in the plasma membrane keep a higher concentration of sodium ions outside the cell and a higher concentration of potassium ions inside, and create a voltage difference, of about 60-100 mV, generally referred to as the resting potential. Since the external surface is positive and the internal surface is negative, the membrane is polarized.
2. Depolarization: When the neuron is stimulated, a small region of the cell's membrane is depolarized to a threshold potential. When this happens, voltage-gated Na channels along the membrane open, and Na+ ions rapidly diffuse into the cell, causing the electrical potential across the cell membrane to be reduced. As Na+ ions continue to diffuse into the cell, an excess of positive ions accumulates inside, and the membrane becomes positively charged inside and negatively charged outside, at that small region. The action potential that is formed is typically about 20 mV. The voltage-gated Na channels then spontaneously close.
4. Propagation: The negatively charged membrane at the small region of the action potential stimulates the adjacent region to become depolarized. Thus the action potential propagates as a wave.
5. Repolarization: By the time the action potential has moved from one small region along the membrane to the adjacent region, the first region has repolarized and returned to its resting potential. Repolarization occurs as the Na+ channels close and K+ channels open, allowing K+ ions to diffuse out of the cell more rapidly, restoring the positive charge to the external surface of the membrane, and the negative charge to the internal surface.
6. The Refractory Period: The refractory period is defined as the time period when an excitable membrane cannot be stimulated. It prevents the action potential from stimulating the region from which it came. In other words, it prevents reverberation between two adjacent regions. Thus, propagation must continue forward. During the refractory period, Na+ ions are actively transported out of and K+ into the cell by the Na—K pumps. The refractory period can be divided into two distinct portions:                i. The absolute refractory period is the time during which no stimulus can initiate a new action potential.        ii. The relative refractory period is the time during which a hyper-threshold stimulus can initiate an action potential.        
The phase propagation process is very rapid, about 3 msec to a region, in myelinated fibers. Neurons typically fire at rates of 100 action potentials per second.
Because of the ‘all-or-nothing characteristic of action potential, conduction is non-decremental, that is, it does not diminish, or ‘die out’ with distance from the initial site of stimulation. This is in marked contrast to conduction in a wire of an electrical circuit.
Neurons may be classified by conduction speed, diameter and the presence or absence of specialized lipoprotein insulation called myelin. The main nerve fibers, of about 2-20 microns in diameter, are myelinated, while the lower branches, down to about 0.2 microns in diameter, are unmyelinated. In myelinated fibers, conduction is saltatory, or by jumps, along the unmeylinated nodes of Ranvier. In unmyelinated nerve fibers, conduction is smooth.
Type A fibers are myelinated and can conduct impulses at 12-120 m/sec. Type B are also myelinated fibers but they only transmit impulses at 3-5 m/sec. Type C fibers are unmyelinated, small in diameter, and their conduction is very slow, at a rate of about 0.2-2.0 m/sec. An example of a Type A fiber is a motor efferent neuron innervating the gastrocnemius. An example of a Type B fiber is an autonomic preganglionic efferent neuron. An example of a Type C fiber is a sensory afferent neuron carrying information about diffused pain.
The refractory period of action-potential propagation makes nerve blocking possible. A number of blocking techniques are presently known for blocking or stimulating motor nerves controlling muscular or glandular activities. These include: (1) collision block; (2) high frequency block; and (3) anodal block.
In high frequency block, high frequency (e.g., 600 Hz) stimulations are used to block the transmission of the action potentials through the nerve fibers.
In anodal block, nerve fibers are locally hyperpolarized by a DC anodal current. If sufficiently hyperpolarized, action potentials are not able to propagate through the hyperpolarized zone and will be blocked. Anodal block is described, for example, in N. J. M. Rijkhof et al., “Acute Animal Studies on the Use of Anodal Block to Reduce Urethral Resistance in Sacral Root Stimulation” IEEE Transactions on Rehabilitation Engineering, Vol. 2, No. 2, pp. 92, 1994, whose disclosure is incorporated herein by reference.
In collision block, artificially induced action potentials are generated by a unidirectional electrode (an electrode adapted for generating an action-potential propagation substantially in one direction) and collide with, and thereby block, the naturally induced action potentials, coming towards them. In essence, the artificially induced action potential at a region along the axon membrane is timed and shaped so that when a naturally induced action potential arrives at that region, the region is in a refractory period, and the naturally induced action potential cannot propagate through it.
Collision block has been described, for example, in C. van den Honert, J. T. Mortimer “A Technique for Collision Blocks of Peripheral Nerve: Single Stimulus Analysis”, IEEE Transactions on Biomedical Engineering, Vol. 28, No. 5, pp 373, 1981, whose disclosure is incorporated herein by reference.
The unidirectional electrode is an important component in collision blocking. Designs of unidirectional electrodes may be found, for example, in the following articles, Ungar I J et al., “Generation of unidirectionally propagating action potentials using a monopolar electrode cuff,” Annals of Biomedical Engineering, 14:437-450 (1986), Sweeney J D et al., “An asymmetric two electrode cuff for generation of unidirectionally propagated action potentials,” IEEE Transactions on Biomedical Engineering, vol. BME-33(6) (1986), and van den Honert C et al., “Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli,” Science, 206(4424):1311-1312 (1979), whose disclosures are incorporated herein by reference.
Additionally, U.S. Pat. No. 4,649,936, to Ungar, et al., dated Mar. 17, 1987, and entitled, “Asymmetric single electrode cuff for generation of unidirectionally propagating action potentials for collision blocking,” whose disclosure is incorporated herein by reference, describes a single electrode, having an asymmetric electrode cuff, which is disposed around a nerve trunk. A signal generator is connected between a cathode disposed asymmetrically in the electrode cuff and an anode disposed in an electrically conductive relationship within the body tissue. The signal generator applies a stimulus signal, which generates unidirectionally propagating action potentials on the nerve trunk. The electrode cuff includes a dielectric sleeve in which the cathode is positioned a first distance from an escape end and a second distance from an arrest end. The first distance is at least 1.7, and preferably about 7, times the second distance. This asymmetry causes a primary or forward stimulus signal current to be correspondingly greater than a secondary or reverse current.
Further work by the same group includes U.S. Pat. No. 4,628,942, to Sweeney, et al., dated, Dec. 16, 1986, and entitled, “Asymmetric shielded two electrode cuff,” whose disclosure is incorporated herein by reference, and which describes an annular electrode cuff positioned around a nerve trunk, for imposing electrical signals on to the nerve trunk for the purpose of generating unidirectionally propagated action potentials. The electrode cuff includes an annular cathode having a circular passage therethrough of a first diameter. An annular anode has a larger circular passage therethrough of a second diameter, which second diameter is about 1.2 to 3.0 times the first diameter. A non-conductive sheath extends around the anode, cathode, and nerve trunk. The anode and cathode are placed asymmetrically to one side of the non-conductive sheath. Specifically, a first length along the electrode sheath between a first end and the cathode is at least twice a second length between the anode and cathode. A third length between the anode and a second end of the conductive sheath is smaller than the first or second lengths. With this geometry, the majority of the current applied to the anode electrode flows to the cathode along desired path segments with lesser amounts of current flowing in the less desired path segments.
Selective blocking relies on some combination of these techniques, for example, using a tripolar electrode formed as a cathode and primary and secondary anodes. In general, nerve stimulation is performed with the cathode. As the current is increased, fibers of lower diameters are “recruited,” or stimulated. At a low current, only A fibers are activated, while at a higher current, both A and B fibers are activated. However, when it is desired to activate, for example, only B fibers, the current is divided between the primary and secondary anodes, such that while the cathode operates at a current that activate both A and B fibers, the primary anode inhibits A fibers, by hyper-polarization tuned specifically for these larger-diameter fibers. Thus an overall activation of B fibers is achieved, with the action potential propagation in the B fibers being towards the secondary anode. In this manner it is possible to predefine a range of nerve-fiber diameters and activate them specifically.
Techniques for selective blocking, have been described, for example, in D. M. Fitzpatrick et al., “A Nerve Cuff Design for the Selective Activation and Blocking of Myelinated Nerve Fibers”, Ann. Conf. of the IEEE Eng. in Medicine and Biology Soc., Vol. 13, No. 2, pp. 906, 1991, describing a tripolar electrode device useful for this purpose. Also see N. J. M. Rijkhoff et al., “Orderly Recruitment of Motoneurons in an Acute Rabbit Model” Ann. Conf. of the IEEE Eng., Medicine and Biology Soc., Vol. 20, No. 5, pp. 2564, 1998; and R. Bratta et al., “Orderly Stimulation of Skeletal Muscle Motor Units with Tripolar Nerve Cuff Electrode”, IEEE Transactions on Biomedical Engineering, Vol. 36, No. 8, pp. 836, 1989. The contents of the foregoing publications are incorporated herein by reference.
As taught by Fitzpatrick et al., the tripolar electrode used for muscle control includes a central cathode flanked on its opposite sides by two anodes. The central cathode generates action potentials in the motor nerve fiber by cathodic stimulation; one anode produces a complete anodal block in one direction so that the action potential produced by the cathode is unidirectional; and the other anode produces a selective anodal block to permit passage of the action potential in the opposite direction through selected motor nerve fibers to produce the desired muscle stimulation or suppression. Further details concerning the construction and operation of such tripolar electrodes are set forth in the above-cited publications incorporated herein by reference.
Additionally, J. F. X. Jones, Y. Wang, and D. Jordan (1995): Heart Rate Response to Selective Stimulation of Cardiac Vagal C-Fibers in Anesthetized Cats, Rats, and Rabbits,” J. Physiol., 489, 203-214, incorporated herein by reference, describes the use of two bipolar electrodes to stimulate only a certain group of fibers (for example, only C-fibers), based on their diameters.
Additionally, commonly owned U.S. Pat. No. 6,600,954 to Cohen et al., dated Jul. 29, 2003, and entitled, “Method and Apparatus for Selective Control of Nerve Fibers,” whose disclosure is incorporated herein by reference, describes a method and apparatus particularly useful for pain control by selectively blocking the propagation of body-generated action potentials traveling through a nerve bundle by using a tripolar electrode device to generate unidirectional action potentials to serve as collision blocks with the body-generated action potentials representing pain sensations in the small-diameter sensory fibers. In the described preferred embodiments there are a plurality of electrode devices spaced along the length of the nerve bundle which are sequentially actuated with delays corresponding to the velocity of propagation of the body-generated action potentials through the large-diameter fibers to produce a “green wave” effect which minimizes undesired anodal blocking of the large-diameter fibers while maximizing the collision blocking of the small-diameter fibers.
Furthermore, commonly owned US Patent Application US20030045914, to Cohen et a., published on Mar. 6, 2003 and entitled, “Treatment of Disorders by Unidirectional Nerve Stimulation,” whose disclosure is incorporated herein by reference, describes an apparatus for treating a condition of a subject. An electrode device is adapted to be coupled to longitudinal nervous tissue of the subject, and a control unit is adapted to drive the electrode device to apply to the nervous tissue a current, which is capable of inducing action potentials that propagate in the nervous tissue in a first direction, so as to treat the condition. The control unit is further adapted to suppress action potentials from propagating in the nervous tissue in a second direction opposite to the first direction.
A problem with nerve activation is a “virtual cathode effect,” or a “virtual anode effect,” which causes some interference, as follows:
As defined by Rattay, in the article, “Analysis of models for extracellular fiber stimulation,” IEEE Transactions on Biomedical Engineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated herein by reference, the activation function (AF) is the second spatial derivative of the electric potential along an axon. In the region where the activation function is positive, the axon depolarizes, and in the region where the activation function is negative, the axon hyperpolarizes. If the activation function is sufficiently positive, then the depolarization will cause the axon to generate an action potential; similarly, if the activation function is sufficiently negative, then local blocking of action potentials transmission occurs. The activation function depends on the current applied, as well as the geometry of the electrodes and of the axon.
For a given electrode geometry, the equation governing the electrical potential is:∇(σ∇U)=4πj
where U is the potential, σ is the conductance tensor specifying the conductance of the various materials (electrode housing, axon, intracellular fluid, etc.), and j is a scalar function representing the current source density specifying the locations of current injection. The activation function is found by solving this partial differential equation for U. If the axon is defined to lie in the z direction, then the activation function is:
  AF  =                    ∂        2            ⁢      U              ∂              z        2            
In a simple, illustrative example of a point electrode located a distance d from the axis of an axon in a uniformly-conducting medium with conductance σ, the two equations above are solvable analytically, to yield:
  AF  =                    I        el                    4        ⁢        πρ              ⁢                            2          ⁢                      z            2                          -                  ⅆ          2                                      (                                    z              2                        +                          ⅆ              2                                )                2.5            
where Ie1 is the electrode current. It is seen that when σ and d are held constant, and for a constant positive Ie1 (to correspond to anodal current), the minimum value of the activation function is negative, and is attained at z=0, i.e., at the point on the nerve closest to the source of the anodal current. Thus, the most negative point on the activation function corresponds to the place on a nerve where hyperpolarization is maximized, namely at the point on the nerve closest to the anode.
Additionally, this equation predicts positive “lobes” for the activation function on either side of z=0, these positive lobes peaking in their values at a distance which is dependent on each of the other parameters in the equation. The positive values of the activation function correspond to areas of depolarization, a phenomenon typically associated with cathodic current, not anodal current. However, it has been shown that excess anodal current does indeed cause the generation of action potentials adjacent to the point on a nerve corresponding to z=0, and this phenomenon is therefore called the “virtual cathode effect.” (An analogous, but reverse phenomenon, the “virtual anode effect” exists responsive to excess cathodic stimulation.)
US Patent Application 20030050677, to Gross, et al., entitled, “Electrode assembly for nerve control,” whose disclosure is incorporated herein by reference, describes an apparatus for applying current to a nerve, the apparatus being designed also to reduce the virtual cathode effect. A cathode is adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve. A primary inhibiting anode is adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve. A secondary inhibiting anode is adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site. For most applications, the secondary anodal current is of lower magnitude than the primary anodal current. In this manner, the “virtual cathode” effect induced by the primary anodal current is minimized. As described hereinabove, the virtual cathode effect can stimulate, rather than block, the generation of action potentials in fibers in a region adjacent to the application of anodal current of a sufficiently high magnitude. In accordance with the teaching of US Patent Application 20030050677, to Gross, et al., application of the primary and secondary anodal currents in appropriate ratios is configured to generally minimize the virtual cathode effect. Typically, but not necessarily, the ratio of the primary to the secondary anodal current ranges from 5:1 to 10:1. Additionally, the apparatus of US Patent Application 20030050677 may include a housing to which the cathode and a plurality of anodes are coupled, wherein one of the anodes is positioned within the housing so as to reduce a virtual cathode effect induced by another one of the anodes.
The Vagus nerve (the tenth cranial nerve) has been the subject of considerable research in nerve stimulation. It is composed of somatic and visceral afferents and efferents, and is responsible for controlling and (or) receiving feedback from various glands, the pharynx, larynx, heart, lungs, liver, stomach, intestine, and uterus. Because of its large number of functions with respect to a range of body systems, the Vagus nerve is preferred in many applications for purposes of modulating the functions of designated organs or portions of the central nervous system.
Nerve blocking along a major nerve trunk such as the Vagus nerve may be achieved by implanting an electrode along the trunk, which is large enough, and visible. Yet, such blocking affects the large plurality of nerve branches that emerge from the trunk, and their respective organs, without discrimination. However, in general, discrimination is important, and it is generally desired to target only a specific organ. Because the nerve fibers leading to the specific organs are very fine, implanting an electrode along it is technically difficult. There is thus a need for activating, inhibiting, and monitoring action-potential propagations along a specific nerve branch, with minimum interference to other nerve branches.